The following includes information that may be useful in understanding the present inventions. It is not an admission that any of the information provided herein is prior art, or relevant, to the presently described or claimed inventions, or that any publication or document that is specifically or implicitly referenced is prior art.
Recent studies have highlighted the importance of the human microbiome in health and disease. However, for the most part the mechanisms by which the microbiome mediates disease, or protection from it, remain poorly understood. Hajishengallis and colleagues have been developing the Keystone-pathogen hypothesis, which highlights the important interactions between flora normally found in healthy humans, diseases associated with alterations in these flora, and the role of the host inflammatory system in the transition between health and a disease state (1). The keystone-pathogen hypothesis holds that certain low-abundance microbial pathogens can orchestrate inflammatory diseases, by remodeling a normally benign microbiota into a dysbiotic one. Hajishengallis and colleagues critically assess the available literature that supports the keystone hypothesis, which may provide a novel conceptual basis for the development of targeted diagnostics and treatments for complex dysbiotic diseases. This work provides an elementary background understanding for use of specific organisms delivered to specific sites in the Gastro-intestinal tract, which is the subject of the instant invention.
As currently understood, probiotics are live non-toxic microbial food supplements that can beneficially affect a host by improving the host's intestinal microbial balance without causing disease. Because probiotic organisms may be altered by antibiotic treatments or for other reasons, they do not permanently colonize in the body. It is therefore important that they be ingested regularly for their health-promoting effects to persist. After ingestion, probiotics typically adhere to a tissue of the host, such as the wall of the intestine or the vagina. Once attached, the desirable bacteria are capable of multiplying and colonizing, thereby enhancing optimal microflora balance. They are used to promote healthy microflora (‘good bacteria “or commensals) balance (good or eubiosis) in the lower GI tract and healthy pH balance (yeast fungus) in the oral cavity, large intestine and vaginal tract and minimize microbial imbalance or dysbiosis. Probiotics characteristics are the following: (1) from human origin; (2) stable and viable, gastric and bile acid resistant; (3) effectively adhere to and colonizing at the site of action; (4) compete with pathogens for adhesion sites; and (5) produce pathogen inhibitory substances, e.g. bacteriocidins and organic acids.
Probiotics provide: (1) normalization of flora (e.g., suppress PPMs, provide for intestinal mucosal integrity, regulation of bowel movement, IBS, etc.); (2) Immunomodulation (e.g., strengthen immunity, alleviate food allergy symptoms, control of IBD, etc.); (3) Metabolic effects (e.g., Production of vitamins to improve digestion, minimize lactose intolerance, lower cholesterol, promote bile acid deconjugates, etc.) and many other benefits. Probiotics are sometimes combined with prebiotics (combination is called Symbiotic) which are range of range of non-digestible dietary supplements, which modify the balance of the intestinal micro flora, stimulating the growth and/or activity of beneficial microorganisms and suppressing potentially deleterious microorganisms. The supplements include oligosaccharides (fructo-oligosaccharides, galacto—oligosaccharides); Inulin, Lactulose, Lactitol and a few select bacterial strains that produce bifidogenic nutrients. In particular, prebiotics promote the proliferation of Bifidobacteria in the colon and also promote the proliferation of Lactobacilli in the small intestine to a certain extent.
There are many nutritional probiotics products currently available and are marketed as dietary supplements with very soft DSHEA type “support health” benefit claims. Probiotic products are marketed in all different types of dosage forms, by way of example liquids, capsules, enteric coated tablets and matrix sustained release formulations for oral administration. They use different mix of bacteria and sometimes are enteric coated and of the type which are conventionally released into duodenal target and would not survive transit to reach the potential target organs, e.g., colon. The normal pH profile of the GI tract changes (up and down) from the stomach to the colon, e.g. the pH of the stomach, duodenum, ileum and colon is in the range of 1-4, 5.5-6, 7.3-8.0 and 5.5-6.5, respectively. In some diseases conditions the pH of the GI tract may be modified, e.g. pH of the ileum in normal is 7.5 to 8.2, while pH of the ileum in Metabolic Syndrome, Type 2 diabetes and Obese subjects is 7.3 to 7.5, as discovered using the SmartPill to examine distal intestinal pH values in health and diseases.
To date it is assumed that there are no published reports of any kind that support any specific US FDA approved clinical efficacy or safety claims, nor delivery to any specific area or specific benefits of the probiotics. All of the current evidence is generated from different systems and has not been utilized for a practical treatment regimen that is directed toward flora replacement strategy prior to our foundation discoveries in Roux-en-Y gastric bypass (RYGB) patients (3). Likewise, no product currently exists that specifically delivers the probiotic organism(s) at the target specific pH of the colon at pH 5.5-6.2. Most of the enteric products release the probiotic to the duodenum at pH 5.5-6.2 and because of degradation in the proximal intestine, organisms released may never actually reach the ileum or the right sided colon. Accordingly, it would be advantageous to develop a platform technology for controlled delivery formulation of oral enhanced probiotics that specifically target to release in the pH environment of the ileum and the colon, for treatment/cure of various diseases (pill in a pill concept). These include the active and prophylaxis treatment for Clostridium difficile infection, and possible treatments of metabolic syndrome in diabetes.